RECURRENT HEPATITIS B AFTER LIVER TRANSPLANTATION

Summary

Principal Investigator: A S F Lok
Abstract: Hepatitis B accounts for approximately 5000 deaths/yr in the United States. Early results with orthotopic liver transplantation (OLT) for hepatitis B were poor with recurrence rates of >80% and 2-year mortality rates of 50%. Recent studies found that continuous high dose IV hepatitis B immune globulin (HBIG) can decrease the rate of reinfection to <20%. However, high dose HBIG is very expensive ($30,000-$50,000/yr) and the efficacy is low in patients with replicative infection pre-OLT. Pilot studies showed that lamivudine (LAM, an oral nucleoside analog which costs $1,200-$1,500 per yr) can decrease the rate of recurrent hepatitis B to <30% during the first post-OLT year but the long-term efficacy is limited by drug resistant mutants. Three pilot studies reported that combination therapy of HBIG and LAM is more effective than either agent alone with recurrence rates <5%, but it is not clear how long HBIG needs to be administered. Given the high costs and the inconvenience of life-long HBIG therapy, there is a need for a prospective, randomized controlled trial to determine if prophylaxis with LAM and short-term HBIG is as effective as LAM and long-term HBIG in the prevention of recurrent hepatitis B post-OLT. The use of antiviral agents with potential activity against LAM resistant HBV mutants, such as adefovir dipivoxil, also needs to be evaluated. The specific aims of our study are: (1) To compare the safety, efficacy and cost-effectiveness of combination therapy with LAM and a 6-month course of HBIG with LAM and a 3-yr course of HBIG in the prevention of recurrent hepatitis B post-OLT. (2) To identify the epidemiological, clinical and virological factors that are associated with recurrent hepatitis B post-OLT. (3) To determine the safety and efficacy of adefovir dipivoxil in the suppression of HBV replication in patients who have developed LAM resistant HBV mutants and to compare the rate of recurrent hepatitis B post-OLT in patients with and without LAM resistant mutants prior to transplant. This is a prospective, randomized, multi-center clinical trial involving 20 liver transplant centers in N. America, to be conducted under an investigator IND 59,167. 290 patients with hepatitis B who are listed for OLT as UNOS status 1 or 2 will be enrolled. Open label LAM will be administered to decrease virus load pre-OLT. Patients will be randomized after OLT to Group I: LAM and 3 yr-course of HBIG or Group II: LAM and 6-month course of HBIG. Patients who develop LAM resistant mutants pre- or post- OLT will additionally receive adefovir dipivoxil. The primary end-point of this trial is the rate of recurrent hepatitis B during the first 3 yr post-OLT. This trial will provide definitive answers whether combination therapy with LAM and a 6-mon course of HBIG is as efficacious and more cost-effective than LAM and a 3-yr course of HBIG in the prevention of recurrent hepatitis B post-OLT. In addition, crucial data will be generated on the efficacy of pre-OLT LAM in virus clearance, incidence and outcome of silent allograft infection, clinical outcome of patients with LAM resistant HBV mutants, and management of patients with LAM resistant mutants.
Funding Period: 2001-06-01 - 2009-12-31
more information: NIH RePORT

Top Publications

  1. ncbi When to start and stop hepatitis B treatment: can one set of criteria apply to all patients regardless of age at infection?
    Bulent Degertekin
    Ann Intern Med 147:62-4. 2007
  2. pmc Impact of virologic breakthrough and HBIG regimen on hepatitis B recurrence after liver transplantation
    B Degertekin
    University of Michigan Health System, Ann Arbor, MI, USA
    Am J Transplant 10:1823-33. 2010
  3. pmc Clinical outcomes of liver transplantation for HBV-related hepatocellular carcinoma: data from the NIH HBV OLT study
    Steven Huy Han
    David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
    Clin Transplant 25:E152-62. 2011
  4. ncbi Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management
    Anna S Lok
    Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109 0362, USA
    Hepatology 46:254-65. 2007
  5. ncbi Presence of intrahepatic (total and ccc) HBV DNA is not predictive of HBV recurrence after liver transplantation
    Munira Hussain
    Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109 0362, USA
    Liver Transpl 13:1137-44. 2007
  6. pmc Outcomes of patients with hepatitis B who developed antiviral resistance while on the liver transplant waiting list
    Melissa K Osborn
    University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
    Clin Gastroenterol Hepatol 5:1454-61. 2007
  7. ncbi Impact of the hepatitis B virus genotype on pre- and post-liver transplantation outcomes
    Paul Gaglio
    Center for Liver Disease and Transplantation, Columbia University College of Physicians and Surgeons, New York, NY, USA
    Liver Transpl 14:1420-7. 2008
  8. pmc Characterization of genotype-specific carboxyl-terminal cleavage sites of hepatitis B virus e antigen precursor and identification of furin as the candidate enzyme
    Kiyoaki Ito
    Liver Research Center, Island Hospital and Warren Alpert School of Medicine, Brown University, Providence, Rhode Island, USA
    J Virol 83:3507-17. 2009
  9. ncbi Liver transplantation outcomes among Caucasians, Asian Americans, and African Americans with hepatitis B
    Natalie Bzowej
    California Pacific Medical Center, San Francisco, CA, USA
    Liver Transpl 15:1010-20. 2009
  10. ncbi Navigating the maze of hepatitis B treatments
    Anna Suk Fong Lok
    Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan 48109, USA
    Gastroenterology 132:1586-94. 2007

Scientific Experts

  • A S F Lok
  • Steven Huy B Han
  • Munira Hussain
  • Stephen N Wong
  • Bulent Degertekin
  • Hyung Joon Yim
  • Natalie Bzowej
  • Paul Gaglio
  • Sukru Emre
  • Terese Howell
  • Melissa K Osborn
  • Scott K Fung
  • Robert Perrillo
  • Cheryl Denham
  • Timothy Siropaides
  • Morton Brown
  • Michael Ishitani
  • Diana Tsui
  • Velimir A C Luketic
  • Eugene Schiff
  • Maria Torres
  • Heidi Togerson
  • Tram Tran
  • Amy Crumley
  • Raymond T Chung
  • Mark Sturdevant
  • Stacy McLeod
  • Donna Harsh
  • Marian Bihrle
  • Val Peacock
  • Robert Gish
  • Maria Martin
  • Emmet Keeffe
  • Jim Imus
  • Joy Peter
  • Rajender Reddy
  • Timothy Pruett
  • Consuelo Soldevila-Pico
  • Emmet B Keeffe
  • Ying Liu
  • B Degertekin
  • Pearl Kim-Hong
  • Javaluyas Aniceto
  • Lucinda Porter
  • Kiyoaki Ito
  • Jamie Zagorski
  • Jessica Tan
  • Tram T Tran
  • Arie Regev
  • K Rajender Reddy
  • Pietro Andreone
  • Carmela Cursaro
  • C T Wai
  • E R Schiff
  • K R Reddy
  • R S Brown
  • E B Keeffe
  • M B Ishitani
  • C Soldevila-Pico
  • T L Pruett
  • S Emre
  • T T Tran
  • V A Luketic
  • Jamie Zagorsk
  • Shuping Tong
  • Robert Brown
  • Kyun Hwan Kim
  • Consuelo Soldevila Pico
  • Aniceto Javaluyas
  • Sundeep Singh
  • Lucinder Porter
  • Pearl Kim Hong
  • Charles Moore
  • Chun Tao Wai
  • Natalie H Bzowej
  • Stephen Wong
  • Timothy L Pruett
  • Robert P Perrillo
  • Robert J Fontana
  • Chi Jen Chu
  • Paul J Gaglio
  • Velimir Luketic
  • Michael B Ishitani
  • Scott Fung
  • Evelien Libbrecht
  • Erwin Sablon
  • T J Davern
  • Pamela Richtmyer
  • J Polson
  • Jorge A Marrero

Detail Information

Publications21

  1. ncbi When to start and stop hepatitis B treatment: can one set of criteria apply to all patients regardless of age at infection?
    Bulent Degertekin
    Ann Intern Med 147:62-4. 2007
  2. pmc Impact of virologic breakthrough and HBIG regimen on hepatitis B recurrence after liver transplantation
    B Degertekin
    University of Michigan Health System, Ann Arbor, MI, USA
    Am J Transplant 10:1823-33. 2010
    ..In conclusion, low rates of HBV recurrence can be accomplished with all the HBIG regimens used when combined with antiviral therapy including patients with breakthrough pre-OLT as long as rescue therapy is administered pre- and post-OLT...
  3. pmc Clinical outcomes of liver transplantation for HBV-related hepatocellular carcinoma: data from the NIH HBV OLT study
    Steven Huy Han
    David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
    Clin Transplant 25:E152-62. 2011
    ..This study presents the final, long-term outcome of patients transplanted for HBV-related HCC in the National Institutes of Health (NIH) HBV OLT Study Group...
  4. ncbi Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management
    Anna S Lok
    Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109 0362, USA
    Hepatology 46:254-65. 2007
    ..Thus, there is a need to standardize nomenclature relating to hepatitis B antiviral resistance, and to define genotypic, phenotypic, and clinical resistance to NA therapy...
  5. ncbi Presence of intrahepatic (total and ccc) HBV DNA is not predictive of HBV recurrence after liver transplantation
    Munira Hussain
    Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109 0362, USA
    Liver Transpl 13:1137-44. 2007
    ..Our findings suggest that occult HBV reinfection occurs in most HBV patients after OLT and continued administration of appropriate prophylactic therapy is important in preventing overt HBV recurrence...
  6. pmc Outcomes of patients with hepatitis B who developed antiviral resistance while on the liver transplant waiting list
    Melissa K Osborn
    University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
    Clin Gastroenterol Hepatol 5:1454-61. 2007
    ..Use of antiviral salvage therapy might decrease this risk...
  7. ncbi Impact of the hepatitis B virus genotype on pre- and post-liver transplantation outcomes
    Paul Gaglio
    Center for Liver Disease and Transplantation, Columbia University College of Physicians and Surgeons, New York, NY, USA
    Liver Transpl 14:1420-7. 2008
    ..Our study suggests that HBV genotypes but not precore or core promoter variants may have an impact on pre- and post-OLT outcomes of hepatitis B patients...
  8. pmc Characterization of genotype-specific carboxyl-terminal cleavage sites of hepatitis B virus e antigen precursor and identification of furin as the candidate enzyme
    Kiyoaki Ito
    Liver Research Center, Island Hospital and Warren Alpert School of Medicine, Brown University, Providence, Rhode Island, USA
    J Virol 83:3507-17. 2009
    ..In conclusion, our study reveals genotypic differences in HBeAg processing and implicates furin as the major enzyme involved in the cleavage of the first and second RXXR motifs...
  9. ncbi Liver transplantation outcomes among Caucasians, Asian Americans, and African Americans with hepatitis B
    Natalie Bzowej
    California Pacific Medical Center, San Francisco, CA, USA
    Liver Transpl 15:1010-20. 2009
    ..Our finding of a higher rate of HBV recurrence among Caucasians needs to be validated in other studies...
  10. ncbi Navigating the maze of hepatitis B treatments
    Anna Suk Fong Lok
    Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan 48109, USA
    Gastroenterology 132:1586-94. 2007
  11. ncbi Antiviral therapy for pre- and post-liver transplantation patients with hepatitis B
    Jessica Tan
    Liver Transpl 13:323-6. 2007
  12. ncbi Low risk of hepatitis B virus recurrence after withdrawal of long-term hepatitis B immunoglobulin in patients receiving maintenance nucleos(t)ide analogue therapy
    Stephen N Wong
    Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109 0362, USA
    Liver Transpl 13:374-81. 2007
    ..Maintenance therapy with NA after discontinuation of long-term HBIG therapy is associated with a low risk of HBV recurrence after OLT in compliant HBV patients...
  13. ncbi Adefovir-resistant hepatitis B can be associated with viral rebound and hepatic decompensation
    Scott K Fung
    Division of Gastroenterology, University of Michigan, Medical Center, 3912 Taubman Center, Ann Arbor, MI 48109 0362, USA
    J Hepatol 43:937-43. 2005
    ..The aim of this study was to describe the clinical course of patients with adefovir-resistant HBV infection...
  14. ncbi Treatment of hepatitis B: who, when, and how?
    Stephen N Wong
    Arch Intern Med 166:9-12. 2006
  15. ncbi Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005
    Hyung Joon Yim
    Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109 0362, USA
    Hepatology 43:S173-81. 2006
    ..Newer antiviral therapies with improved efficacy and decreased risk of resistance may lead to a complete revision of the chapter on the natural history of chronic HBV infection on the occasion of the golden jubilee of Hepatology...
  16. pmc Sensitive line probe assay that simultaneously detects mutations conveying resistance to lamivudine and adefovir
    Munira Hussain
    Division of Gastroenterology, University of Michigan Medical Center, 1500 East Medical Center Drive, 3912 Taubman Center, Box 0362, Ann Arbor, Michigan 48109 0362, USA
    J Clin Microbiol 44:1094-7. 2006
    ..Our study confirms that this assay can simultaneously detect the presence of lamivudine and adefovir resistance mutations in clinical samples, has a high degree of concordance with sequencing, and can detect mutants earlier...
  17. ncbi Antiviral options for the treatment of chronic hepatitis B
    Melissa K Osborn
    Division of Infectious Diseases, Emory University School of Medicine Atlanta, GA, USA
    J Antimicrob Chemother 57:1030-4. 2006
    ..Development of drug resistance is a major concern with long-term treatment. Even with successful therapy, patients remain at risk for reactivation of viral replication and require lifelong monitoring...
  18. ncbi Evolution of multi-drug resistant hepatitis B virus during sequential therapy
    Hyung Joon Yim
    Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109 0362, USA
    Hepatology 44:703-12. 2006
    ..De novo combination therapy may prevent the emergence of multi-drug resistant mutants...
  19. ncbi Comparison of clinical outcomes in chronic hepatitis B liver transplant candidates with and without hepatocellular carcinoma
    Stephen N Wong
    Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109 0362, USA
    Liver Transpl 13:334-42. 2007
    ..In conclusion, despite more advanced liver disease and a lower rate of transplantation, ITT survival of patients listed for HBV-cirrhosis was comparable to those with HBV-HCC, possibly related to beneficial effects of antiviral therapy...
  20. pmc A genotype-independent real-time PCR assay for quantification of hepatitis B virus DNA
    Ying Liu
    Division of Gastroenterology, University of Michigan Medical Center, 1500 East Medical Center Dr, 3912 Taubman Center, Box 0362, Ann Arbor, MI 48109 0362, USA
    J Clin Microbiol 45:553-8. 2007
    ..We have established a real-time PCR assay that is genotype independent and can accurately quantify a wide range of HBV DNA levels. Further studies of additional samples are ongoing to validate the genotype independence of our assay...
  21. ncbi Clinical outcome and virological characteristics of hepatitis B-related acute liver failure in the United States
    C T Wai
    Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA
    J Viral Hepat 12:192-8. 2005
    ..Further studies are needed to determine if HBV genotypes play a role in the outcome of acute HBV infection...